Insulin is a kind of hormones produced by β cells in Langerhans islets of pancreas, and plays an important role in maintaining homeostasis of living body by affecting lipid metabolism and protein metabolism as well as sugar metabolism via insulin receptors which are present in target tissues of insulin such as skeletal muscles, liver and fats. Examples of the effects of insulin in respective target tissues include promotion of absorption of glucose from blood into muscle cells and adipocytes, promotion of glycogen production in liver and muscle tissues, inhibition of gluconeogenesis in liver, promotion of glucose consumption and fatty acid synthesis in the adipocytes, and inhibition of degradation of lipids.
The insulin resistance means a state that the cells, organs or individuals require larger amounts of insulin than those typically required in order to obtain respective effects of insulin, that is, a state of impaired insulin effects where sensitivity to insulin is decreased. From results of past epidemiologic investigations, hypertension, diabetes, hyperlipidemia (hypertriglyceridemia and hypo-HDL-cholesterolemia), obesity and the like are considered insulin resistance-based pathosis. The insulin resistance causes insufficient effects of insulin in the sugar metabolism, results in compensatory hyperinsulinemia for maintaining blood sugar level, whereby hyperglycemia and glucose intolerance occur and diabetes is promoted by exhaustion of pancreatic β cells. Furthermore, the hyperinsulinemia enhances activation of sympathetic nerves and promotes sodium absorption of kidney to cause hypertension, and also induces postprandial hyperlipidemia and hyperuricemia, an increase in plasminogen activator inhibitor-1 (PAI-1), and the like.
Meanwhile, the insulin resistance induces abnormal lipid metabolism caused by the insufficient effects of insulin, and free fatty acid (FFA) released from adipocytes increases in liver to promote synthesis of triglyceride (TG), resulting in hypertriglyceridemia. Furthermore, activity of lipoprotein lipase (LPL) generally having high insulin sensitivity is decreased in the insulin resistant state, so degradation of TG is decreased and the hypertriglyceridemia is additionally exacerbated. Furthermore, with exacerbation of diabetes, complications such as retinopathy, nephropathy and gangrene caused by angiopathy occur so that cardiac infarction and cerebral infarction that are arteriosclerotic diseases exacerbate, and hypertension exacerbates cardiovascular diseases. As described above, the insulin resistance is considered to be significantly involved in exacerbation of complicated pathosis (Non-patent Document 1).
In recent years, from results of analysis of organ-specific gene expression, it was revealed that various physiologically active substances are secreted from fat tissues, and the fat tissues thus has been recognized to be not only energy storage tissues but also the largest endocrine organ in a living body. Endocrine factors derived from the fat tissues are generically called adipocytokines, and play important roles in maintenance of homeostasis in metabolism. However, it is considered that, in a case of obesity, that is, a state where fats are accumulated, an excessive or a too small amount of adipocytokines are produced and secreted, and the balance of the adipocytokines is disrupted, resulting in insulin resistance.
The adipocytokines are classified into two groups: one that enhances insulin sensitivity; and one that elicits insulin resistance, representative examples of the former group include adiponectin, leptin, AMPK (AMP-dependent protein kinase) and the like. In particular, it has been reported that the adiponectin has an effect of canceling insulin resistance and an effect of inhibiting gluconeogenesis in liver (Non-patent Document 2).
Meanwhile, examples of the adipocytokines that elicit insulin resistance include tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) that is a kind of inflammatory chemokine, and resistin in addition to the aforementioned FFA and PAI-1. In particular, it has been reported that TNF-α has an effect of eliciting the insulin resistance by inhibiting tyrosine phosphorylation of an insulin receptor and IRSI (insulin receptor substrate 1) in the insulin signal transduction mechanism so that the effect of insulin is attenuated. Furthermore, it has been reported that, in the insulin resistant state, the MCP-1 level in a living body is increased and mRNA of GLUT4 (glucose transporter-4) that is a glucose-transporting carrier, PPARY (peroxisome proliferator-activated receptors) that is an intranuclear receptor, β3AR (β3-adrenergic receptor) that is a kind of β type catecholamine receptor of an adipocyte, and aP2 (adipocyte fatty-acid-binding protein 2) that is a fatty-acid-binding protein are reduced. Therefore, MCP-1 is considered to be a causative agent of decreasing insulin sensitivity (Non-patent Documents 3, 4 and 5).
As agents for improving insulin resistance, biguanide agents that inhibit gluconeogenesis mainly in liver, and thiazolidine derivatives that improve the insulin sensitivity of muscles and fat tissues have been developed. Those agents have already been permitted as diabetic medicines, and also used for treatment of arteriosclerosis. The thiazolidine derivatives as represented by troglitazone and pioglitazone are each considered to act as a ligand for peroxisome proliferator-activated receptor (PPAR) that is an intranuclear receptor-type transcription factor to promote differentiation of adipocytes, thereby improving insulin resistance.
In addition, an agent for improving insulin resistance containing adiponectin or their genes as an active ingredient (Patent Document 1) a preventive and/or therapeutic agent for diseases caused by insulin resistance containing a substance having affinity to bombesin receptor subtype 3 (BRS-3) as an active ingredient (Patent Document 2), a free fatty acid (FFA) decreasing agent containing a pyrrole derivative as an active ingredient (Patent Document 3) and the like have been disclosed as the agents for improving insulin resistance. Furthermore, a composition for improving insulin resistance containing acetic acid and an ion or salt thereof as an active ingredient (Patent Document 4), an agent for improving insulin resistance comprising a fatty oil containing particular diglyceride and/or monoglyceride (Patent Document 5) and the like have been disclosed as the agents containing a substance derived from a food or drink as an active ingredient.
Plant sterols such as β-sitosterol, campesterol and stigmasterol have been known to have a decreasing effect on blood cholesterol by inhibition of absorption of cholesterol, and practical use thereof has been attempted by adding them as a fat composition to edible oil. Furthermore, an anti-obesity agent and a lipid metabolism-improving agent containing a cholestenone compound as an active ingredient which is synthesized by using plant sterols such as β-sitosterol and campesterol as a starting material have been disclosed (Patent Documents 6 to 8, and Non-patent Document 6).
Furthermore, an adiponectin secretion promoter containing an extract from at least one of rice bran, shimeji mushroom, chrysanthemum, rye, white birch and Spanish Jasmine (Alpinia zerumbet), and cycloartane type triterpene or cycloartenol and/or (24S)-24,25-dihydroxycycloartanol which are derivatives of cycloartane type triterpene have been disclosed (Patent Document 9).
The genus Aloe belonging to liliaceae plant is a group of plants including Aloe vera (Aloe barbadenisis Miller), Aloe arborescens (Aloe arborescens Miller var. natalensis Berger) and the like, and they are empirically known to have various efficacies. For example, immunosuppression improving agents containing a butanol fraction of an aloe extract or a loin (Patent Document 10), an agent related to improving blood glucose levels (Patent Documents 11 to 14), a preventive and improving agent for obesity (Patent Document 15) and the like are disclosed, but the improving effect on insulin resistance of the plants belonging to the genus Aloe has not been reported.    [Patent Document 1] International Publication NO. WO2003/63894 pamphlet    [Patent Document 2] Japanese Patent Laid-open NO. 10-298100    [Patent Document 3] Japanese Patent Laid-open NO. 08-12573    [Patent Document 4] Japanese Patent Laid-open NO. 2002-193797    [Patent Document 5] Japanese Patent Laid-open NO. 2001-247473    [Patent Document 6] Japanese Patent Laid-open NO. 07-165587    [Patent Document 7] Japanese Patent Laid-open NO. 11-193296    [Patent Document 8] Japanese Patent Laid-open NO. 2001-240544    [Patent Document 9] Japanese Patent Laid-open NO. 2005-68132    [Patent Document 10] Japanese Patent Laid-open NO. 08-208495    [Patent Document 11] Japanese Patent Laid-open NO. 60-214741    [Patent Document 12] Japanese Patent Laid-open NO. 2003-286185    [Patent Document 13] U.S. Pat. No. 4,598,069    [Patent Document 14] U.S. Patent Application Publication No. 2003/0207818    [Patent Document 15] Japanese Patent Laid-open NO. 2000-319190    [Non-patent Document 1] Insulin resistance and lifestyle-related diseases, Ed. Kazuaki Shimamoto, Shindan to Chiryosha, 2003, pp. 1-5    [Non-patent Document 2] Adiposcience, vol. 1, No. 3, 2004, pp. 247-257    [Non-patent Document 3] Proceedings of the National Academy of Sciences, vol. 100, 2003, pp. 7265-7270    [Non-patent Document 4] Nature, vol. 389, 1997, pp. 610-614    [Non-patent Document 5] The Netherlands Journal of Medicine, vol. 61, NO. 6, 2003, pp. 194-212    [Non-patent Document 6] Hormone Metabolism Research, vol. 37, 2005, pp. 79-83